Comparing the prognostic and predictive utility of serum thymidine kinase 1 and CA 15-3 in patients with hormone receptor positive metastatic breast cancer starting first-line endocrine therapy in SWOG S0226.
Authors: Erin Frances Cobain, William E. Barlow, Costanza Paoletti, Mattias Bergqvist, Amy Williams, Hanna Ritzen, Rita S. Mehta, Julie R. Gralow, Gabriel N. Hortobagyi, Kathy S. Albain, Lajos Pusztai, Priyanka Sharma, Andrew K. Godwin, Alastair Mark Thompson, Daniel F. Hayes, James M. Rae
Journal: Journal of Clinical Oncology (2023)

1076 Background: Serum levels of thymidine kinase 1 activity (TKa), a fundamental enzyme in DNA synthesis and cellular proliferation, are prognostic of benefit from endocrine therapy (ET) in patients (pts) with hormone receptor positive (HR+) metastatic breast cancer (MBC) who participated in SWOG S0226, a prospective randomized trial comparing anastrozole vs. anastrozole and fulvestrant given in 4 week cycles. The assay for TKa (DiviTum TKa) was FDA approved in July 2022 for monitoring of postmenopausal HR+ MBC pts. The assay for circulating MUC1, CA 15-3, is routinely utilized in monitoring of pts with MBC. We compared the prognostic and predictive utilities of CA 15-3 and TKa in pts from S0226. Methods: TKa was measured in 1725 sera from 432 pts while CA 15-3 was measured in 1298 sera from 326 pts at baseline (BL), cycles 2, 3, 4 and 7. Prespecified cutoff levels of ≥ 250 DuA and ≥ 30 U/mL were considered high for TKa and CA 15-3 respectively. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier and Cox regression stratified by prior adjuvant tamoxifen use. To examine markers over time, a landmarked Cox regression analysis was done starting at initiation of Cycle 4. BL and recent (Cycle 3 if available, otherwise Cycle 2) markers were assessed for simultaneous prediction of subsequent PFS and OS. Results: BL TKa was elevated in 190/432 (44%) and CA 15-3 was elevated in 254/326 (78%). Agreement between assays was 53%. Pts with high versus low BL TKa had significantly worse PFS (median 11.6 vs. 17.2 months, HR = 1.68, 95% confidence interval (CI) 1.37-2.06) and OS (median 34 vs. 58 months, HR = 2.16, 95% CI 1.73-2.70) whereas pts with high versus normal BL CA 15-3 had no significant difference in PFS (median 13.6 vs. 16.1 months, HR = 1.23, 95% CI 0.93-1.62) but worse OS (median 45 vs. 66 months, HR = 1.82, 95% CI 1.30-2.53). A multivariable Cox model with both markers shows only TKa as being prognostic for PFS (TKa HR = 1.61, 95% CI 1.28-2.03; CA 15-3 HR = 1.21, 95% CI 0.91-1.59), but both prognostic for OS (TKa HR = 2.09, 95% CI 1.61-2.71; CA 15-3 HR = 1.70, 95% CI 1.22-2.38). In the landmarked multivariable analysis, positive TKa at BL was a strong predictor of PFS (HR = 1.65, 95% CI 1.28-2.14), but recent TKa was not (HR = 1.25, 95% CI 0.93-1.68). In contrast, positive CA15-3 at BL was not a predictor of PFS (HR = 0.73, 95% CI 0.46-1.17), but recent CA15-3 was (HR = 1.97, 95% CI 1.26-3.06). Conclusions: BL TKa is highly prognostic in pts with HR+ MBC initiating first-line systemic ET, with low BL TKa conferring superior prognosis. In contrast, CA 15-3 is only modestly prognostic at BL, but is prognostic after 3 cycles of treatment. These hypothesis-generating data suggest further study is needed to determine how these biomarkers should be employed in a complementary manner to monitor response to systemic therapy in HR+ MBC. Clinical trial information: NCT00075764 .